Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To improve the clinical outcome of allogeneic hematopoietic stem cell transplantation from an unrelated donor, the identification of human leukocyte antigen (HLA) alleles responsible for immunologic events such as graft-versus-host disease (GVHD), engraftment failure, and graft-versus-leukemia effect is essential. Genomic typing of HLA-A, -B, -C, -DRB1, and -DQB1 was retrospectively performed in 1298 donor-patient pairs in cases where marrow was donated from serologically HLA-A, -B, and -DR compatible donors. Single disparities of the HLA-A, -B, -C, or -DRB1 allele were independent risk factors for acute GVHD, and the synergistic effect of the HLA-C allele mismatch with other HLA allele mismatches on acute GVHD was remarkable. HLA-A and/or HLA-B allele mismatch was found to be a significant factor for the occurrence of chronic GVHD. HLA class I (A, B, and/or C) allele mismatch caused a significantly higher incidence of engraftment failure than HLA match. Significant association of HLA-C allele mismatch with leukemia relapse was not observed. As the result of these events, HLA-A and/or HLA-B allele mismatch reduced overall survival remarkably in both standard-risk and high-risk leukemia cases, whereas the HLA-C mismatch or HLA-class II (DRB1 and/or DQB1) mismatch did not. Furthermore, multiple mismatch of the HLA locus was found to reduce survival in leukemia cases. Thus, the role of the HLA class I allele in unrelated bone marrow transplantation was elucidated. Notably, HLA-C alleles had a different mode from HLA-A or -B alleles for acute GVHD and survival.
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PMID:The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. 1201 Aug 26

An 8-month-old girl had acute myelogenous leukemia (EAB M2) that relapsed 5 months after diagnosis during intensive consolidation chemotherapy. She underwent bone marrow transplantation (BMT) from an HLA-A, -B, -C and -DR phenotypically matched, but one locus DRB1 genotypically mismatched unrelated donor, but rejection occurred.Subsequently, she received reduced-intensity transplant (fludarabine/cytosine arabinoside/cyclophosphamide) from one locus HLA-A-mismatched, but DRB1 genotypically matched unrelated cord blood stem cells and remission was induced by acute GVHD (grade II) that progressed to chronic GVHD with involvement of the skin, liver, and gastrointestinal tract. In this case, it seems that remission was induced by an adequate graft-versus-leukemia effect and mild chronic graft-versus-disease due to the HLA-A difference more than DRB1 matched between the patient and the cord blood stem cells.
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PMID:Successful reduced-intensity stem cell transplant from one-locus HLA-mismatched unrelated cord blood after rejection of unrelated bone marrow in an infant with myelogenous leukemia. 1218 99

Until a decade ago, hematopoietic stem cell transplantation from related donor mismatched at two or three HLA-A, -B or DR loci was largely unsuccessful in leukemia patients because of severe graft-versus-host disease in unmanipulated bone marrow transplants and graft failure in extensively T-cell-depleted transplants. The breakthrough came with the use of a megadose of T-cell-depleted hematopoietic progenitor cells. Donor-vs-recipient natural killer cell alloreactivity also plays a role in facilitating engraftment and in preventing relapse of acute myeloid leukemia. Event-free survival and transplant-related mortality for high risk acute leukemia patients treated at less advanced stages of disease compare favourably with reports from unrelated matched transplants.
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PMID:Hematopoietic stem cell transplantation from full-haplotype mismatched donors. 1235 53

Aims of this study were to verify whether reduction in transplant-related mortality (TRM) of children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) given allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated volunteers has occurred over time and to investigate the role of other variables on the probabilities of relapse, TRM and event-free survival (EFS). We compared results obtained in 26 children given HSCT before January 1998 with those of 37 patients transplanted beyond that date. In all donor-recipient pairs, histocompatibility was determined by serology for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 antigen. High-resolution molecular typing of HLA class I antigens was employed in 20 of the 37 children transplanted more recently. Probability of both acute and chronic GVHD was comparable in the two groups of patients. In multivariate analysis, children transplanted before January 1998, those with T-lineage ALL and those experiencing grade II-IV acute GVHD had a higher relative risk of TRM at 6 months after transplantation. Relapse rate was unfavorably affected by a time interval between diagnosis and relapse <30 months. The 2-year probability of EFS for children transplanted before and after 1 January 1998 was 27% (10-44) and 58% (42-75), respectively (P = 0.02), this difference remaining significant in multivariate analysis. EFS of unrelated donor HSCT in children with ALL in second CR has improved in the last few years, mainly due to a decreased TRM. This information is of value for counseling of patients with relapsed ALL.
Leukemia 2002 Nov
PMID:Improvement over time in outcome for children with acute lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from unrelated donors. 1239 66

We studied the graft-versus-leukaemia (GVL) effect in 185 patients with haematological malignancies who underwent unrelated donor haematopoietic stem cell transplantation (HSCT) at Huddinge University Hospital between May 1991 and June 2001. Ninety-five were in first CR/CP and 90 in later stages. Most (86%) of them had a HLA-A, -B and -DRbeta1 matched donor. Conditioning usually consisted of total body irradiation and cyclophosphamide, and GVHD prophylaxis of cyclosporine and methotrexate. In the multivariate risk-factor analysis of relapse, we found that disease stage beyond CR1/CP1 (P = 0.02), acute GVHD 0-I (P = 0.02), absence of chronic GVHD (P = 0.02) and ALL (P = 0.02) were independent risk factors for relapse. The incidence of relapse in those with acute GVHD grade II was 18% vs 46% in those with no or grade I (P = 0.04). In patients with or without chronic GVHD, the incidences of relapse were 32% and 48%, respectively (P < 0.01). The best RFS was seen in patients with chronic GVHD. No difference in RFS was seen in patients with no, mild or moderate acute GVHD. Risk factors for relapse after HSCT with unrelated donors were: acute lymphoblastic leukaemia, disease stage beyond CR1/CP1, absence of chronic GVHD and no, or mild acute GVHD. Overall and relapse-free survival were not improved by the occurrence of acute GVHD.
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PMID:The graft-versus-leukaemia effect in haematopoietic stem cell transplantation using unrelated donors. 1243 99

Analysis of HLA restriction specificity is one of the important steps in characterizing T cell clones. This usually requires either a panel of HLA-typed cells or HLA cDNA transfectants. Although preparation of HLA cDNA transfectants is laborious, utilization of transfectants is advantageous when a suitable panel is not available due to linkage disequilibrium or rarity of the HLA allele of interest. In this report, we describe an efficient and rapid HLA cloning and expression system. Three sets of PCR primers specific for HLA-A, B and C loci were designed by extensively sequencing 5'- and 3'- untranslated regions of HLA class I genes. The PCR-amplified products were introduced into modified Phoenix retrovirus vectors containing a puromycin resistant gene under the control of a LTR promotor. Gibbon ape leukemia virus (GALV)-pseudotyped retrovirus was produced and infected into B-lymphoid cell lines. Following expansion in selection media, more than 80% of cells expressed transduced HLA at a comparable level to that normally expressed. These results indicate that locus-specific PCR cloning and utilization of GALV-pseudotyped retroviral vector can be an effective and relatively efficient tool for constructing a panel of different HLA transfectants.
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PMID:Efficient cloning and expression of HLA class I cDNA in human B-lymphoblastoid cell lines. 1244 20

Dendritic cell (DC) plays a key role in antitumor immune response. However, there is a deficiency of DC function in the majority of leukemia patients. It is a novel idea that expanding DC in vitro and enhancing their antitumor immune function and DC-based tumor vaccines may be used as an efficient immune therapy for leukemia. In the project, the condition to induce DC from myeloid leukemia cell lines and its anti-leukemia response were investigated. HL-60, K562 and THP-1 cells were cultured with various combinations of cytokines for inducing DC. The morphologic features were analyzed with optical and electron microscopy. The phenotype of DC was detected by FCM with CD1a, CD40, CD80, CD86, HLA-A, B, C and HLA-DR monoclonal antibodies. The ability of DC stimulating lymphocyte proliferation was observed by allo-mixed lymphocyte reaction using (3)H-TdR incorporation. Cytotoxicity assay was measured by (51)Cr-release method. The level of IL-12 and IFN-gamma in supernatant of DC culture was measured by ELISA. It was proved that the DCs derived from K562, HL-60 and THP-1 cells showed a typical morphology of dendritic cell. The induced cells expressed the surface differentiation antigens of DC. A high expression of phenotypes was found in HL-60-DC and THP-1-DC stimulated by GM-CSF + IL-4 + TNF-gamma and K562-DC with GM-CSF + IL-4 + IL-12. The DCs from the 3 leukemia cell lines stimulated allo-MLR and CTL reaction strongly. Different contents of IL-12 were detected in the supernatants of DC culture and IFN-gamma in the coculture of DC and blood mononuclear cells. It is concluded that the myeloid leukemia cells are able to be induced DCs by cytokines in vitro. The different leukemia cells need different cytokines and cultural conditions. DCs derived from leukemia cells express phenotype of antigen-presenting cells. They have the ability of stimulating T lymphocyte proliferation and inducing CTL reaction to clear leukemia cells, and the DCs secrete IL-12 and increase secretion of IFN-gamma by T cells.
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PMID:[Study on induction of dendritic cells from myeloid leukemia cell lines and their antitumor immune function]. 1251 92

A rapid and accurate method of DNA typing for HLA was established to compensate the unsatisfactory serological typing for HLA before transplantation. DNA typing for HLA using by reverse polymerase chain reaction with sequence-spcific oligo probe (reverse PCR-SSOP) could detect HLA-A(*0101 - 8001) and B(*07021 - 8201). The results showed that HLA-AB alleles were successfully analysed in 60 matching subjects and 16 control DNAs from UCLA by reverse PCR-SSOP without false negtive and false positive results. The results were concordance with those of UCLA. The error rate of serological typing was 6.4% for HLA-A and 7.4% for HLA-B. The serological typing missed HLA-A24 and HLA-B46 for two patients with leukemia respectively. Our results suggest that DNA typing for HLA by reverse PCR-SSOP has proved to be a high-resolution, high-specificity, rapid and accurate technique, suitable for clinical application with a greater precision than serological typing.
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PMID:[Typing of HLA-AB by Reverse PCR-SSOP and Clinical Application] 1257 80

Downregulation of MHC class Ia molecule expression is a widespread mechanism used by tumor cells to escape antitumor T-cell-mediated immune responses. However, it is not known why NK cells cannot lyse these MHC class-Ia-deficient tumor targets. Tumors must select additional routes of escape from NK cells. An attractive hypothesis is that the aberrant expression of nonclassical HLA class Ia molecules in tumors provides the required inhibitory signal to NK cells, rendering tumor cells resistant to NK lysis. To analyze the possible role of HLA-E molecules in providing tumor cells with an NK escape mechanism, we studied the cell surface expression of this HLA class Ib molecule in a variety of tumor cell lines with well-defined HLA class Ia alterations. Tests were done with the monoclonal antibody 3D12 recognizing cell surface HLA-E molecules. Our results indicate that HLA-E was mainly detected in leukemia-derived cell lines. In addition, HLA-E was detected in tumor cell lines of different origin. This expression was related with the availability of free beta(2)-microglobulin (beta(2)m) in the cytoplasm of tumor cells. Expression was detected in tumor cell lines showing an imbalance in heavy chain/beta(2)m expression, particularly in tumor cell lines with alterations in the expression of heavy-chain genes. Several lines of evidence favor these conclusions: (1) In the FM55 and NW145 melanoma tumor systems, the reduction in HLA class Ia expression paralleled the increased cell surface detection of HLA-E. (2) A cervical tumor (808) and a melanoma cell line (R22.2) expressing a single HLA-A1 allele also expressed HLA-E. (3) The addition of human beta(2)m to tumor cell lines that expressed the HLA-E(G) allele increased HLA-E cell surface expression. (4) There was no HLA-E cell surface expression in tumor cell lines with total loss of HLA class Ia expression, including cell lines with low transcription of HLA class I heavy chains or with beta(2)m mutations. Our findings suggest that the biological consequences of these cumulative genetic and molecular changes in tumor cells lead to the appearance of HLA-E in a limited number of tumor cell lines with peculiar phenotypic and genotypic characteristics, namely: HLA-class Ia downregulation, free beta(2)m and HLA-E(G) genotype. The aberrant HLA-E expression might be of particular biological relevance in those HLA tumor phenotypes that express a single HLA-A allele when NK inhibition is markedly reduced due to the downregulation of HLA-B and -C alleles.
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PMID:Analysis of HLA-E expression in human tumors. 1261 9

Exploiting the graft-versus-leukemia (GVL) effect in mismatched transplants requires its separation from graft-versus-host disease (GVHD). We generated leukemia-specific cytotoxic T lymphocytes (CTL) in three haplotype-mismatched, two class I-mismatched and two single HLA-A locus-matched stimulator-responder pairs. Six patients with chronic myelogenous leukemia and one patient with acute myeloid leukemia transformed from MDS were studied. CTL generated after 10 days stimulation with unselected leukemic peripheral blood mononuclear cells inhibited leukemic CFU-GM colony growth (>85% at 10:1 effector:target ratio) with no third-party colony inhibition. In five pairs, responders were cultured separately with leukemia cells, PHA-B or LCL from the stimulator. After 2-4 restimulations, the T cell repertoire was examined by flow analysis using Vbeta-specific antibodies. Test cultures (but not controls) showed preferential expansion of 1-4 Vbeta families either common to two or more stimulators or unique to a particular stimulator. Notably, we elicited leukemia-specific TCR Vbeta expansions on four out of five occasions. In two pairs, responder cells selected for the appropriate leukemia-specific Vbeta family were shown to have leukemia-specific cytotoxicity. These leukemia-restricted T-cells were CD8+ or CD4+ and CD25+ or CD57+. The results support the development of strategies to selectively deplete GVHD and conserve GVL reactivity in mismatched transplants.
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PMID:Tissue-restricted T cell alloresponses across HLA barriers: selection and identification of leukemia-restricted CTL in HLA-mismatched stimulator-responder pairs. 1290 Jul 73


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